Mitochondrial defects are associated with the development of diseases such as type 2 diabetes (T2D). Studies in mice and in human tissues, by researchers at the University of Michigan, have now found that dysfunctional mitochondria trigger a response that affects the maturation and function of pancreatic β-cells. They found that in T2D dysfunctional mitochondrial quality control engages a retrograde signaling program that impairs cellular identity and maturity in β-cells, and also in other cell types evaluated.
Reporting their results in Science (“Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues”), first author Emily M. Walker, PhD, a research assistant professor of internal medicine, together with senior author Scott A. Soleimanpour, MD, director of the Michigan Diabetes Research Center, and colleagues, concluded: “Together, our results demonstrated that mitochondrial quality control plays a central role in the maintenance of cell identity and maturity in metabolic tissues that may be essential to the development of T2D and other metabolic disorders.” They suggest their findings could point to new approaches for treating or preventing metabolic disorders.
Patients with T2D are unable to produce enough insulin or use the insulin produced by their pancreas to keep their blood sugar at normal levels. Mitochondria are essential for generating energy that fuels cells and helps them function. Several studies have shown that insulin-producing pancreatic β-cells in patients with type 2 diabetes have abnormal mitochondria and are unable to generate energy. Yet, these studies were unable to explain why the cells behaved this way. “Mitochondrial damage is a hallmark of metabolic diseases, including diabetes, yet the consequences of compromised mitochondria in metabolic tissues are often unclear,” the researchers wrote.
Since it was first proposed that mitochondrial dysfunction may represent what the authors described as “a broad unifying mechanism in T2D,” mitochondrial defects have been described in various tissues. “The impact of mitochondria in T2D pathogenesis has been further bolstered by findings that β-cell mitochondrial gene expression and oxidative phosphorylation defects precede the development of T2D in humans,” the team continued. “Moreover, several human genetic studies support links between mitochondria and T2D.”
Walker continued, “We wanted to determine which pathways are important for maintaining proper mitochondrial function.” To do so, the team damaged three components that are essential for mitochondrial function: their DNA, a pathway used to get rid of damaged mitochondria, and one that maintains a healthy pool of mitochondria in the cell.
“In all three cases, the exact same stress response was turned on, which caused β-cells to become immature, stop making enough insulin, and essentially stop being β-cells,” Walker said. “Our results demonstrate that the mitochondria can send signals to the nucleus and change the fate of the cell.” The researchers also confirmed their findings in human pancreatic islet cells.
The results prompted the team to expand their search into other cells that are affected during diabetes. The team repeated their mouse experiments in liver cells and fat-storing cells and saw that the same stress response was turned on. Both cell types were unable to mature and function properly.
“Although we haven’t tested all possible cell types, we believe that our results could be applicable to all the different tissues that are affected by diabetes,” Soleimanpour said.
Regardless of the cell type, the researchers found that damage to the mitochondria did not cause cell death. This observation brought up the possibility that if they could reverse the damage, the cells would function normally. To do so, they used a drug called ISRIB that blocked this stress response. They found that after four weeks, the β-cells regained their ability to control glucose levels in mice. “… pharmacologic blockade of the integrated stress response in vivo restored β-cell identity following loss of mitochondrial quality control,” the authors stated.
The team is working on further dissecting the cellular pathways that are disrupted and hopes that they will be able to replicate their results in cell samples from diabetic patients.
“Losing your β-cells is the most direct path to getting type 2 diabetes,” Soleimanpour said. “Through our study, we now have an explanation for what might be happening and how we can intervene and fix the root cause.”
The authors concluded, “Targeting mitochondrial retrograde signaling may therefore be promising in the treatment or prevention of metabolic disorders.”
